1. Field of the Invention
This invention relates generally to methods for modulating angiogenesis, tumorigenesis, and/or vascular permeability. In particular, this invention relates to methods for the use of compositions that affect the apelin/APJ signaling pathway to treat patients suffering from various angiogenesis-related diseases or conditions.
2. Background Art
Under normal physiological conditions, humans and animals undergo angiogenesis only in very specific situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonic development, and formation of the corpus luteum, endometrium, and placenta. Unregulated angiogenesis occurs in a number of diseases and conditions, such as tumor growth and metastasis. Both controlled and unregulated angiogenesis are thought to proceed in a similar manner. Endothelial cells and pericytes, surrounded by a basement membrane, form capillary blood vessels. Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a “sprout” off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel.
APJ is a cell surface receptor belonging to the G protein-coupled receptor family and has seven transmembrane domains. APJ is related to the angiotensin II receptor and has been described as being a coreceptor involved in the mediation of HIV-1 neuropathogenesis. A natural ligand of APJ was identified and named apelin (APJ endogenous ligand). The apelin polypeptide is initially produced as a 77 amino acid protein (preproapelin) that is cleaved to produce cleavage products of 36 amino acids, 17 amino acids, and 13 amino acids. The peptide consisting of the C-terminal 13 amino acids of the apelin polypeptide is necessary and sufficient for the ability of an apelin polypeptide to interact with APJ.
Some methods have been achieved which effectively modulate angiogenesis under certain conditions. For example, AVASTIN is an anti-VEGF antibody produced by Genentech that is currently in clinical trials for treatment of breast cancer, colorectal cancer, small cell lung cancer, and renal cancer, and that has been shown to have an anti-angiogenic effect on certain tumor types. AVASTIN has received FDA approval for use in patients having a colorectal cancer that has disseminated. Similarly, MACUGEN is an aptamer from Eyetech/Pfizer that targets VEGF and that has a demonstrated anti-angiogenic effect with regard to macular degeneration (Eyetech Study Group, 2003, Opthalmology 110(5):979-86).
To date, various polypeptides have been described that stimulate angiogenesis (e.g. VEGFs, FGFs, PDGFB, EGF, LPA, HGF, PD-ECF, IL-8, angiogenin, TNF-alpha, TGF-beta, TGF-alpha, proliferin, and PLGF) or inhibit angiogenesis (e.g. ENDOSTATIN, ANGIOSTATIN, and thrombospondin). Although some methods have been achieved which effectively modulate angiogenesis in certain situations, clearly more therapeutics are needed to treat a broader range of diseases and conditions, as well as to increase the efficacy of the methods that already exist. Therefore, what is needed in the art are new compositions and methods for modulating angiogenesis to inhibit the undesired growth of blood vessels associated with certain diseases and conditions. What is also needed are methods and compositions for modulating tumorigenesis and/or permeability of a tumor. What is further needed are new methods for promoting angiogenesis in patients suffering from diseases or conditions that are indicated by decreased vascularization. Moreover, what is also needed are methods for identifying therapeutic agents capable of modulating angiogenesis effectively and safely in a patient.